This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding the brain mechanisms involved in tobacco dependence is an important step toward reducing the high rate of relapse associated with current behavioral programs and phamacological treatments for smoking cessation. This proposal seeks to define the efficacy, safety and tolerability of repetitive Transcranial Magnetic Stimulation (rTMS) for treating tobacco dependence. Tobacco dependence is a serious public health problem and cigarette smokers exhibit substantial relapse following treatment. A concept central to this proposal is that "quitting" necessitates a conscious choice not to smoke (to delay gratification) and this choice is influenced by the balance of activity between fronto-parietal systems that process the value of rewards and limbic systems that favor drive states leading to immediate gratification. Aim 1 will determine how different levels of cortical excitation, induced by different rTMS frequencies, influence reward choices and how they alter cigarette consumption. Additionally, Aim 2 will determine how limbic activation due to acute nicotine withdrawal modifies these effects in aim 1. Twenty 20 non-smoking subjects and 20 active smokers will receive two levels of high frequency rTMS and comparable sham stimulation (method we developed using electrical scalp stimulation) delivered over left prefrontal cortex. Smokers will also crossover between nicotine satiation and withdrawal conditions to determine how rTMS can modify limbic activation associated with withdrawal. The Junior investigator of this project, Christine Sheffer, Ph.D., is an expert in all aspects of the development and implementation of evidence-based treatment programs for tobacco dependence and she has direct experience with the cognitive aspects of this proposal in prior work as a co-investigator on an NIH grant with Warren Bickel. Dr. Sheffer represents a new link with the UAMS College of Public Health and brings her experience in epidemiological research to the CTN. This project will instigate a translational research effort in Dr. Sheffer's work by allowing her to build on earlier training in the electrophysiological activity of the prefrontal cortex in addiction. This project is also expected to spark parallel investigations in the Molecular Core such as examining gene expression following high intensity rTMS in rodents and work in the Animal Electrophysiology Core examining the amplitude and frequency of spontaneous cortical oscillations following rTMS. The overall goal is for Dr Sheffer to gain data sufficient for winning her first R01 from the NIH.